Under PAR-07-024, Ancillary Studies to Major Ongoing NIDDK and NHLBI Clinical Research Studies NIDDK, we are proposing to conduct a study which aims to examine the natural history of Acute Kidney Injury (AKI) arising in patients with sepsis. Sepsis is found in more than 50% of critically-ill patients with AKI.3 The NIH has recently funded a large therapeutic trial of early septic shock (P50 GM076659). This trial, Protocolized Care for Early Septic Shock (ProCESS), will randomize 1935 patients at 19 centers to three different treatment arms. The opportunity to study patients from the ProCESS cohort presents us with an historic opportunity to prospectively conduct a large natural history study ancillary to an extensive multi-center trial in a setting which is most likely to result in AKI. Our proposal, Protocolized Goal-directed Resuscitation of Septic Shock to Prevent Acute Kidney Injury (ProGReSS AKI), will examine the effect of protocolized resuscitation on the development of AKI. We also seek to explore mechanisms underlying the effect of the intervention and to evaluate markers of renal injury and repair in order to help select patients for future interventional trials. In keeping with the NIH roadmap, in order to understand the clinical utility of this work, we will build a clinical risk prediction model that will consider biomarkers and clinical variables. We have organized these tasks as three specific aims: 1. test the hypothesis that protocolized resuscitation prevents or lessens severity or duration of AKI, 2. determine which pathophysiologic derangements (inflammation, ischemia, oxidative stress, and coagulation/ thrombosis), in combination or individually, are associated with the development of AKI, and 3. determine whether biomarkers can predict AKI and recovery from AKI in the setting of sepsis. Part of our study will include home visits, for which we have opted to separate from the parent trial so as to avoid any loss of enrollment incurred by the ancillary study. We will re-contact ProCESS subjects after discharge from the hospital and follow them at five time points for three years. Through this part of the study, we will determine if protocolized resuscitation is more effective in improving long term outcomes (survival, renal recovery, reduced progression of CKD) in the entire cohort as well as in the subpopulation that has evidence of AKI by biomarkers (biomarker-positive AKI).